A study of patient‐reported pain during bone marrow aspiration and biopsy using local anesthesia alone compared with local anesthesia with intravenous midazolam coadministration at a tertiary academic hospital in South Africa

Abstract Introduction During the bone marrow aspiration and biopsy (BMAB) procedure, patients report pain of widely variable intensity. There is limited literature on the factors associated with the pain. The use of local anesthesia (LA) only is still widespread although it does not abolish the pain. Midazolam is the most commonly used benzodiazepine for conscious sedation. Our center introduced universal midazolam sedation unless there is a contraindication to its use, 4 years ago. This study assessed the impact of the universal use of intravenous midazolam for BMAB compared to use of LA only. The factors associated with the pain of BMAB, were analyzed. Methods A retrospective cross‐sectional study was performed on adult patients who had a BMAB procedure from July 1, 2018 to March 30, 2019. A questionnaire incorporating a visual analog pain scale, was used for data collection. Results A total of 182 BMAB procedures were included in the study. Pain was reported in all procedures performed under LA and only in 29.1% of procedures performed with midazolam. Age, sex, race, level of education, body mass index (BMI), indication and diagnosis had no influence on pain. Patients who had previous BMAB experienced less pain. Experience of operator had a significant effect on pain. Midazolam dose showed a negative correlation with pain. Conclusion LA only is not enough to abolish pain of BMAB. Midazolam conscious sedation used with LA reduces pain to acceptable levels. Patients with previous experience of BMAB under midazolam premedication reported less pain. Furthermore, the experience of operator reduced the pain significantly.


| INTRODUCTION
Bone marrow aspiration and biopsy (BMAB) is essential for the diagnosis, staging and monitoring of hematological disorders. BMAB also has an important role in the investigation of nonhematological condition such as fever of unknown origin and the diagnosis of infectious diseases, storage disorders and infiltration of the bone marrow by nonhematological malignancies. 1 The procedure has evolved over time, with focus on easier and repeatable collection of bone marrow leading to full standardization of the procedure in the 1970s. 2 BMAB is a painful procedure and the pain and anxiety associated with it, are variable and significant. The pain ranges from negligible mild pain, to distressing severe pain. There are limited studies focusing on the pain experienced during BMAB, the factors that influencing the pain and its management. 3,4 BMAB is usually performed as an outpatient procedure by trained clinicians of variable experience. The best site for the procedure is the iliac crest, posteriorly or anteriorly. Sternal puncture is performed in some situations, in which case only bone marrow aspiration is possible and sternal core biopsy is strictly prohibited.
Bone marrow aspiration of the tibia can be performed in pediatric patients. Lignocaine (1% or 2%) is used for infiltrating the skin, subcutaneous tissue and periosteum. The standard technique should yield about 2 ml of bone marrow aspirate and a core biopsy about 20 mm length. A larger volume of aspirate is required for more investigations such as immunophenotyping, cytogenetics/molecular studies and microbiological cultures if needed. 5,6 The limited trials undertaken to reduce the pain associated with BMAB have not changed clinical practice and pain remains a heavy burden on hematology patients and the doctors performing the procedure. So far, there are insufficient evidence-based guidelines to ameliorate pain resulting from BMAB. 7 The management of the pain and anxiety becomes more critical because hematology patients often require several BMAB procedures.
Several factors influencing the pain experienced during BMAB have been studied. These include sex, age, body mass index (BMI), level of education, adequacy of information provided before the procedure, previous BMAB experience, level of expertise of the doctor performing the procedure (operator) and the duration and difficulty of the procedure. The results of the few studies focused on pain management during BMAB are contradictory. 3,4,7 Several pharmacological and nonpharmacological methods have been proposed for pain reduction in patients undergoing BMAB. 3 A local anesthetic (LA), usually lignocaine or a similar drug, is used to anesthetize the skin, subcutaneous tissue, and periosteum before the procedure. 5 Conscious sedation is often used. Oral or intravenous benzodiazepines such as lorazepam, midazolam, and diazepam are the most commonly used sedatives for BMAB. 8 In the United Kingdom, intravenous midazolam is routinely used for the BMAB procedure. 8 Besides reducing anxiety and pain perception, benzodiazepines induce amnesia in most patients. 9 Its rapid onset of action, short half-life and the ease of availability of its antidote, flumazenil, make midazolam especially attractive in the setting of BMAB.
Chakupurakal et al. 8 in a randomized controlled trial showed the superiority of the administration of midazolam with local anesthesia over Entonox in pain relief and reducing the recall of the procedure in patients undergoing BMAB.
It is the recall of any past pain which causes anxiety and may contribute to pain perception. In the study by Chakupurakal et al.,8 amnesia occurred in most patients who received midazolam sedation which reportedly made their BMAB experience acceptable. This made patients prefer midazolam sedation for subsequent BMAB.
Studies showed reduced pain intensity during BMAB performed with midazolam administration in conjunction with LA. Naumann et al. 10 in a prospective study, compared the effect of relaxation (music and facultative instruction on how to relax), anxiolytic drug (midazolam), analgesic drug (piritramid), and placebo on pain reduction and anxiety in patients undergoing BMAB. Patients who received midazolam showed decreased pain intensity and increased threshold of pain compared to the other three groups in early and late evaluation, after 2 weeks. 10 Glannoutosis et al. 11 in a clinical trial, showed lower pain scores in patients who received midazolam in conjunction with local anesthesia (lignocaine) compared with patients who received local anesthesia only. The mean pain score by Visual Analog Score (VAS) was 1 in the midazolam group versus 3 in patients who received only LA. There was a lower level of apprehension toward having another BMAB in patients who received midazolam, however, the time required to perform the procedure was longer when using conscious sedation with an average of 30 min versus 21 min in patients receiving LA only. 11 Stenstrup et al. 12 evaluated the effect of using midazolam and LA for reducing anxiety and pain during BMAB and demonstrated that using midazolam and LA was comparable with the previous regimen of using opioids and lorazepam with the advantage of less side effects such as over sedation, which was a concern with using the combination of opioids and lorazepam.
This study aimed to assess the impact of the use of intravenous midazolam premedication for the BMAB procedure, using patientreported pain scoring. Furthermore, the factors associated with the attributes of the patient-reported pain were determined.

| MATERIALS AND METHODS
A retrospective cross-sectional study was performed on adult patients (18 years old and more) who underwent the BMAB procedure at a day surgery operating theater (X-block theater) over Patients who had BMAB during the study period were interviewed during their normal follow-up visits to the hematology clinic. Participants signed written informed consent to respond to the questions, to have their medical records viewed, and for their anonymized aggregated results to be published. Interviews were conducted over a 2-month period by the principal investigator assisted by registered nurses who translated for those patients with limited English language ability. Patients were asked to answer an assigned questionnaire (Appendix S1).
A numerical rating scale (NRS) was used to categorize the pain experienced by the patient during the BMAB. 13 It was explained to the patient as 0 no pain at all and 10 the worst imaginable pain ever. Pain scores were classified on an 11-point scale from 0 to 10 as 0 equals no pain, (1-3/10) mild pain, Continuous data (age) was expressed as mean, median, and interquartile range (IQR). Categorical data were expressed as numbers and percentage. Evaluation of the association between variables and pain was performed by using the Mann-Whitney test and Chi-square test. A p-value ≤ 0.05 signifies statistical significance.
Ethics approval for the study was granted by Stellenbosch University's Human Research Ethics Committee. Ethics number; S19/ 03/066.

| RESULTS
One hundred and forty-nine patients were enrolled on the study; 68    Table 5).  Table 5).

| DISCUSSION
Midazolam is the benzodiazepine most commonly used for sedation in medical procedures, especially for procedures outside the operating room. Its anxiolytic, sedative, and amnesia effects are of rapid onset and short duration, all of which are desirable attributes in the day-surgery or bedside procedure settings. 15 The majority of the procedures were performed under midazolam premedication and a minority received local anesthesia only. Patients with a contraindication to midazolam use received local anesthesia only. The contraindications included, patients with chronic heart failure, acute kidney injury, decreased lung function, and recreational drug abuse.
Our study shows that using local anesthesia only is not enough to abolish the pain of BMAB. All of the procedures performed with local anesthesia only resulted in pain. In sharp contrast, only 29.1% of procedures performed with midazolam sedation resulted in pain.
Furthermore, the mean pain score was considerably lower in the midazolam premedication group compared with those who received local anesthesia only.
In a prospective interventional study, Naumann et al. 10 showed reduced pain intensity and increased tolerance of pain when  18 on the other hand, are contrary to our findings, they found that females reported a higher level of pain than males.
This study showed no difference in reported pain between patients regardless of the level of education. Furthermore, the reported degree of understanding of the BMAB had no influence on the pain experienced by the patient.
The level of education may be an important factor in the patient's ability to understand the explanation of the procedure. Wynia et al. 19 found that limited patient literacy affects communication with patients regarding patient health care in general. In turn, patient understanding of the procedure may have an influence on pain perception and reporting. Gendron et al. 20 showed a significant reduction in pain scores in well-informed patients. Degen et al. 17 showed that the patients who were less informed about key aspects of the BMAB procedure were more likely to experience pain than those who understood what the procedure entails.
This study comprises all the officially recognized ethnic groups in South Africa; Colored(mixed race), White, Indian and Asian. There was no difference in the reported pain after analysis by ethnic group.
This is similar to the findings of Talamo et al. 18 Studies have shown that there may be significant differences among ethnic groups with regard to pain perception. 21 In view of South Africa's ethnic diversity, it was necessary to interrogate the role of ethnicity in the pain reported in this study.
Our study showed that BMI had no effect on the pain reported by patients. This study found no statistically significant correlation between the patient's diagnosis and pain, which is consistent with the findings of Gendron et al. 20 Bone pain is part of the disease process in almost all multiple myeloma, in some acute leukemia and in other hematological conditions. 24, 25 We, therefore, aimed to investigate the role of the underlying disease in the pain experience by our participants.
We showed a significant decrease in pain with increase in the experience of the operator. Previous studies were inconsistent.
Degen et al. 17 showed no effect of operator experience on patient reported pain. Kuball et al. 26 in a prospective study showed reduction of duration of procedure with increased experience of the operator which influence pain.

| LIMITATIONS
The questionnaire was applied at variable periods after the BMAB procedure with a minimum 2-week gap. This makes it difficult to assess the role of patient memory in general and the role of the midazolam-induced amnesia.

| CONCLUSION
This study showed that local anesthesia is not enough to abolish the pain of BMAB and that midazolam is effective in pain control.

ACKNOWLEDGMENTS
We would like to thank the following people: Dr. Fatima Bassa for her assistance and the Registered Nurses, Carmen Strydom and Abongile Ntulo for their help with English interpretation for Afrikaans and Xhosa language speakers. We are grateful to the late Prof Birhanu Ayele for his assistance with the initial statistics and data management plan. We dedicate this article to his memory.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
All data associated with this study are available from the corresponding author via Email: zivanai@sun.ac.za.

TRANSPARENCY STATEMENT
The lead author Zivanai Cuthbert Chapanduka affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.